Dengue virus (DV) causes dengue fever (DF) and dengue hemorrhagic fever/dengue shock Syndrome (DHF/DSS), the most prevalent arthropod-borne viral illness in humans worldwide. Both clinical and in vitro laboratory studies have implicated immune-based mechanisms for the manifestations of DHF. Due to the lack of an adequate animal model for DV infection, the immunopathogenic mechanisms of DHF are not yet fully elucidated. As a first step towards understanding the role of the immune system in DV infection in vivo. this proposal aims to optimize a mouse model for DV infection by systematically evaluating novel routes of infection, different viral and mouse strains, and co-injection of immunomodulatory compounds (Specific Aim 1). Since the chemokine network is important in orchestrating anti-viral immune responses and evidence supports a role for chemokines in the immunopathogenesis of DHF, we hypothesize that chemokines (particularly CCL5) participate in the clearance of virus in mice challenged with DV. Thus, Specific Aim 2 is to define the in vivo expression pattern and function of CCL5 in mice with primary DV infections. The long-term goal of this work is to examine the contribution of chemokines to the immunopathogenesis of DHF in vivo.